Mucin Phenotype Research Articles

HER2 expression and its clinicopathological features in resectable gastric cancer

A recent randomized controlled trial (Trastuzumab for Gastric Cancer [ToGA] study) established standard scoring criteria of human epidermal growth factor receptor 2 (HER2) for gastric cancer and demonstrated the efficacy of trastuzumab for treating metastatic gastric cancer. The aim of the present study was to evaluate the frequency of HER2-positive cases by application of the standard criteria in patients with resectable gastric cancer and to examine the relationships between HER2 expression and prognosis, mucin phenotype, p53 status, and clinicopathological features. A total of 213 patients were included in this retrospective study. All tumor samples were examined for HER2 expression by immunohistochemistry (IHC), HER2 amplification by in situ hybridization, and mucin and p53 expression by staining for CD10, MUC2, MUC5AC, MUC6, and p53. HER2-positive tumors were identified in 25 patients (11.7%). HER2-positive cases were more frequently found in men, older patients, and in the intestinal histological type (P=0.0048, 0.0309, and <0.0001, respectively). Although no association was found between HER2 overexpression and mucin phenotype, the expression of CD10 and p53 was significantly correlated with HER2 positivity (P=0.0079 and 0.013). The overall survival of HER2-negative and -positive patients was not significantly different. However, in patients with stage III/IV, overall survival was worse in HER2-positive patients (P=0.0149). In a comparison between dual-color in situ hybridization (DISH) and fluorescence in situ hybridization (FISH), four IHC2+/3+ cases that were DISH-positive were judged as negative by FISH. Our study indicated that HER2 expression was less frequent in resectable gastric cancer than in metastatic gastric cancer. The impact of HER2 expression on survival was limited. DISH was superior to FISH for evaluating cases with limited HER2 expression.

Upregulation of HOXA10 in gastric cancer with the intestinal mucin phenotype: reduction during tumor progression and favorable prognosis

Gastric cancer (GC) is one of the most common malignancies worldwide. Better knowledge of the changes in gene expression that occur during gastric carcinogenesis may lead to improvements in diagnosis, treatment and prevention. In this study, we screened for genes upregulated in GC by comparing gene expression profiles from microarray and serial analysis of gene expression and identified the HOXA10 gene. The aim of the present study was to investigate the significance of HOXA10 in GC. Immunohistochemical analysis demonstrated that 221 (30%) of 749 GC cases were positive for HOXA10, whereas HOXA10 was scarcely expressed in non-neoplastic gastric mucosa except in the case of intestinal metaplasia. Next, we analyzed the relationship between HOXA10 expression and clinicopathological characteristics. HOXA10 expression showed a significant inverse correlation with the depth of invasion and was observed more frequently in the differentiated type of GC than in the undifferentiated type of GC. HOXA10 expression was associated with GC with the intestinal mucin phenotype and correlated with CDX2 expression. Furthermore, the prognosis of patients with positive HOXA10 expression was significantly better than in the negative expression cases. 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide and wound healing assay revealed that knockdown of HOXA10 in GC cells by short interfering RNA transfection significantly increased viability and motility relative to the negative control, indicating that HOXA10 expression inhibits cell growth and motility. These results suggest that expression of HOXA10 may be a key regulator for GC with the intestinal mucin phenotype.

Mucin phenotypes and macroscopic shape of multiple hyperplastic polyps together with two carcinomas in the stomach.

The patient was a 57-year-old Japanese woman who had been identified as having anemia and hypoproteinemia by a local group medical check-up. Esophagogastroduodenoscopy revealed an elevated lesion of 35mm in diameter on the posterior wall of the gastric antrum, surrounded by multiple polyps. The elevated lesion was diagnosed as an adenocarcinoma on the basis of biopsy, and total gastrectomy was performed. Histological examination of entire resected stomach revealed two lesions of intramucosal carcinoma together with multiple hyperplastic polyps. To investigate the mucin phenotypes and carcinogenesis of these lesions, immunohistochemical analyses of MUC2, MUC5AC, MUC6, CD10, Ki-67 and p53 protein expressions were performed in 17 hyperplastic polyps and two cancerous lesions. Expression of the MUC6 positive glands beneath the surface foveolar epithelium of hyperplastic polyps caused a morphological change from sessile to pedunculated, suggesting that this was also involved with cancerous changes. The case reported herein seems to be extremely interesting in terms of elucidating the process whereby gastric cancer arises from hyperplastic polyps.

Recent Progress in Carcinogenesis, Progression and Management of Upper GI Cancer: The 21st Hiroshima Cancer Seminar--the 5th Three Universities' Consortium International Symposium, 6 November 2011, International Conference Center Hiroshima

The 21st Hiroshima Cancer Seminar focused on recent progress of carcinogenesis, progression and management of upper gastrointestinal cancers. β-Catenin and p120 mediate peroxisome proliferator-activated receptor δ-dependent proliferation induced by Helicobacter pylori in gastric epithelia. Helicobacter pylori CagA plays an important role in stomach carcinogenesis via altered signal transduction and cell polarity by interactions with several host proteins. Inflammation caused by H. pylori infection is responsible for inducing aberrant DNA methylation. The gastric gland mucin-specific αGlcNAc plays dual roles in preventing gastric cancer, inhibition of H. pylori infection and suppression of tumor-promoting inflammation. Information obtained from transcriptome dissection greatly contributes to understanding the molecular character of each mucin phenotype of gastric cancer. The standardized biomarkers will serve as good predictive and prognostic markers for gastric cancer. A microRNA expression profile may be useful for the diagnosis of gastric cancer. Bone marrow-derived mesenchymal stem cells may provide an advantageous microenvironment for re-acquisition of stemness of gastric cancer cells. Recent progress in molecular biology research has enabled the clinical development of molecular targeting agents for gastric cancer, such as trastuzumab. The target molecule-based inhibition of the stromal reaction in the microenvironment may hold promise as an effective anti-tumor therapy. Since robotic surgery is feasible and safe, and provides adequate and precise lymph node dissection, it may be one of the good options for gastric cancer in the near future.

Cytokeratin Expression Profiling in Gastric Carcinoma: Clinicopathologic Significance and Comparison with Tumor-Associated Molecules

Objective: The expressions of cytokeratin (CK) 7 and 20 have been studied in various primary and metastatic carcinomas, and their determination may help distinguish the site of origin of metastatic carcinomas. However, little is known about the molecular basis that determines variations in CK patterns in gastric cancers (GCs). The aim of the present study was to analyze the CK expression patterns in a large number of GCs and to investigate how the CK patterns correlate with clinicopathologic parameters, histology, mucin phenotype or several tumor-related molecules. Methods and Results: We immunohistochemically examined the CK7/CK20 patterns, mucin expression profiles (MUC5AC, MUC6, MUC2 and CD10), and the cancer-related molecules (CDX2, p53, EGFR and β-catenin), using a tissue microarray with 870 GCs. The GCs were divided into four patterns; 17% of CK7+/CK20+, 57% of CK7+/CK20–, 9% of CK7–/CK20+ and 17% of CK7–/CK20. GCs with the CK7–/CK20– pattern demonstrated a close relation to undifferentiated adenocarcinoma. CK7 expression was significantly correlated with the expression of MUC5AC and MUC6, while CK20 expression was correlated with MUC2 and CDX2. There were statistically significant associations between CK expression patterns and mucin phenotypes. Conclusion: These results indicate that the CK7/CK20 expression patterns in GCs demonstrated different clinicopathologic features and molecular signatures.

Mucinous borderline‐like tumor of the gastrointestinal type arising from mature cystic teratoma of the ovary and its immunohistochemical cytokeratin and mucin phenotype

Malignant transformation is rarely seen in the disease course of mature cystic teratoma (MCT) of the ovary. Adenocarcinoma arising from MCT is especially rare. We herein present the case of a premenopausal woman with a mucinous borderline-like tumor arising from a MCT. Based on the histological transition between the borderline-like tumor and gastrointestinal elements of the MCT, we consider that the tumor derived from teratomatous gastrointestinal epithelium. Immunohistochemistry showed that the proliferating mucinous cells were diffusely positive for cytokeratin 20 and partially positive for cytokeratin 7. MUC5AC was partially positive, whereas MUC2 and MUC6 were positive in a small number of tumor cells. The immunophenotype of cytokeratins and mucins in the present case was compatible with malignant transformation of the teratomatous gastrointestinal epithelium.

MUC5AC/β-catenin expression andKRASgene alteration in laterally spreading colorectal tumors

To clarify differences in mucin phenotype, proliferative activity and oncogenetic alteration among subtypes of colorectal laterally spreading tumor (LST). LSTs, defined as superficial elevated lesions greater than 10 mm in diameter with a low vertical axis, were macroscopically classified into two subtypes: (1) a granular type (Gr-LST) composed of superficially spreading aggregates of nodules forming a flat-based lesion with a granulonodular and uneven surface; and (2) a non-granular type (NGr-LST) with a flat smooth surface and an absence of granulonodular formation. A total of 69 LSTs, comprising 36 Gr-LSTs and 33 NGr-LSTs, were immunohistochemically stained with MUC2, MUC5AC, MUC6, CD10 (markers of gastrointestinal cell lineage), p53, β-catenin and Ki-67 antibodies, and examined for alteration in exon 1 of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and exon 15 of v-raf murine sarcoma viral oncogene homologue B1 (BRAF) by polymerase chain reaction followed by direct sequencing. Histologically, 15 Gr-LST samples were adenomas with low-grade dysplasia (LGD), 12 were high-grade dysplasia (HGD) and 9 were adenocarcinomas invading the submucosa (INV), while 12 NGr-LSTs demonstrated LGD, 14 HGD and 7 INV. In the proximal colon, MUC5AC expression was significantly higher in the Gr-type than the NGr-type. MUC6 was expressed only in NGr-LST. MUC2 or CD10 did not differ. P53 expression demonstrated a significant stepwise increment in progression through LGD-HGD-INV with both types of LST. Nuclear β-catenin expression was significantly higher in the NGr-type. Ki-67 expression was significantly higher in the Gr-type in the lower one third zone of the tumor. In proximal, but not distal colon tumors, the incidence of KRAS provided mutation was significantly higher in the Gr-type harboring a specific mutational pattern (G12V). BRAF mutations (V600E) were detected only in two Gr-LSTs. The two subtypes of LST, especially in the proximal colon, have differing phenotypes of gastrointestinal cell lineage, proliferation and activation of Wnt/β-catenin or RAS/RAF/extracellular signal-regulated kinase signaling.

Gastric Adenocarcinoma of Fundic Gland Type: Report of Three Cases

Recently, fundic gland type gastric adenocarcinoma (GA-FG) has been reported as a new entity. This report describes GA-FG among Koreans for the first time. From March 2008 to July 2010 we identified only three cases of GA-FG out of over 6,000 GAs resected by endoscopy or surgery. Cell differentiation by mucin proteins, pepsinogen-I, and H+/K+-ATPase was evaluated. All three cases were male patients and diagnosed as early stage GA. Histologically, GA-FGs were well-differentiated adenocarcinoma with pale gray-blue, basophilic columnar or cuboidal cells and mildly enlarged nuclei, resembling chief cells. All three cases were positive for pepsinogen-I and were classified as gastric mucin phenotype. Among three histologic subtypes of GA-FG, since tumors were mainly composed of chief cells, our three cases were classified as chief cell predominant type. In conclusion, GA-FG is very rare among Koreans and pepsinogen-I and MUC6 expression are typical immunohistochemical findings in GA-FG suggesting differentiation toward fundic glands.

Clinicopathological characteristics of human epidermal growth factor receptor 2-positive Barrett's adenocarcinoma

To compare the clinicopathological characteristics of human epidermal growth factor receptor 2 (HER2)-positive and HER2-negative Barrett's adenocarcinoma in Japan. We performed immunohistochemical analysis of HER2 in 30 samples taken from patients with Barrett's adenocarcinoma and dual color in situ hybridization in cases showing 2+ reactions. We compared the clinicopathological characteristics of HER2-positive and HER2-negative patients. HER2 positivity was identified in 8 (27%) carcinoma samples. We found that HER2 expression was associated with p53 overexpression (100% vs 52.6% in pT1 tumor; 100% vs 54.5% in all stage tumor, P < 0.05) and protruding lesions at the early disease stage. There was no association between the mucin phenotype of the carcinomas and prognosis. HER2 expression and low clinical stage were unexpectedly different between Barrett's adenocarcinoma patients and gastric cancer patients, but the macroscopic features may be associated with earlier diagnosis in these patients. Our results suggest that HER2-positive Barrett's adenocarcinomas are associated with p53 overexpression and lesion protrusion at the early disease stage.

Relationship between alpha-methylacyl–coenzyme A racemase expression and mucin phenotype in gastric cancer

Alpha-methylacyl-coenzyme A racemase controls β-oxidation of branched-chain fatty acid and their derivatives. Many investigators have described alpha-methylacyl-coenzyme A racemase expression in various neoplasias and their precursor lesions. Although there have been a few reports regarding alpha-methylacyl-coenzyme A racemase expression in gastric neoplasia, these reports did not discuss the relationship between alpha-methylacyl-coenzyme A racemase expression and mucin phenotype. This study analyzed alpha-methylacyl-coenzyme A racemase expression of gastric carcinomas with regard to mucin phenotype. Alpha-methylacyl-coenzyme A racemase expression was evaluated in 85 cases of gastric biopsies including gastric epithelial neoplasia and nonneoplasia and in 108 cases of surgically resected early gastric cancer. In biopsy cases, alpha-methylacyl-coenzyme A racemase was more highly expressed in neoplasia (69.7%, 23/33) than in nonneoplasia (0%, 0/42) (P = .001). Alpha-methylacyl-coenzyme A racemase was overexpressed in 20.0% (2/10) of cases that were indefinite for neoplasia, and the 2 positive cases were ultimately diagnosed as adenocarcinoma. In resected cases of early gastric adenocarcinoma, alpha-methylacyl-coenzyme A racemase expression significantly correlated with mucin phenotype (P = .003), but not with tumor progression, histologic classification, or clinicopathologic features. Alpha-methylacyl-coenzyme A racemase expression was significantly higher in intestinal-phenotype carcinoma (90.2%, 37/40) than in gastric-phenotype carcinoma (56.3%, 18/31) (P = .006) and also correlated with an increase in CDX2 expression (P = .018) and a decrease in MUC5AC expression (P = .048). This tendency was observed in all histologic types. Our results indicate that alpha-methylacyl-coenzyme A racemase is a useful marker for distinguishing gastric neoplasia from nonneoplasia even at an early stage. Alpha-methylacyl-coenzyme A racemase expression is associated with mucin phenotypes of gastric neoplasia, particularly with the expression of CDX2 and MUC5AC.

Nuclear atypia grading score is a useful prognostic factor in papillary gastric adenocarcinoma

To investigate nuclear atypical in papillary gastric adenocarcinoma (PGA). Hundred cases of PGA were classified into two groups according to nuclear pleomorphism and nuclear polarity; these groups were designated as high nuclear grade and low nuclear grade. Correlations between nuclear grade and clinicopathological features were evaluated for prognostic value. In order to evaluate which types of biological factors influence nuclear atypia, the expression of gastric-type mucin phenotype, p53, HER2 and Ki-67 detected by immunohistochemistry and DNA ploidy detected by laser scanning cytometry. The high nuclear grade group correlated with deeper wall invasion, the presence of lymphatic and venous invasion and the positivity of lymph node metastasis. High nuclear grade was an independent prognostic factor for disease-free survival. Moreover, significant correlations were observed between high nuclear grade and positivity of gastric-type mucin phenotype, p53 and HER2 and DNA aneuploidy. Nuclear grade could be a new and useful morphological predictor for high malignant potential in PGA.

Liver-Intestine Cadherin in Intraepithelial Neoplasia of Intrahepatic Cholangiocarcinoma

Liver-intestine cadherin (LI-cadherin) is a member of the cadherin superfamily and aberrant expression of LI-cadherin is associated with intestinal metaplasia. The aim of this study was to identify factors associated with LI-cadherin expression in biliary intraepithelial lesions of intrahepatic cholangiocarcinoma (ICC). We evaluated the immunoreactivity of LI-cadherin, MUC2, CDX2, MUC5AC and HGM, according to the grade of biliary intraepithelial lesion in 16 resected specimens of ICC without hepatolithiasis. A total of 168 biliary intraepithelial lesions were classified into four grades: reactive change (42 lesions), biliary intraepithelial neoplasia (BilIN)-1 (10 lesions), BilIN-2 (40 lesions) and BilIN-3 (76 lesions). Biliary intraepithelial lesions were classified into three mucin phenotypes: null (46 lesions), gastric (97 lesions) and gastrointestinal phenotype (25 lesions). LI-cadherin expression was found in 45 (27%) of 168 biliary intraepithelial lesions. BilIN-2/3 (p<0.001), gastrointestinal phenotype (p=0.006) and CDX2 expression (p=0.002) were significantly associated with LI-cadherin expression. Logistic regression analysis revealed that BilIN-2/3 (p=0.002) was the only independently significant factor associated with LI-cadherin expression. The grade of BilIN independently correlates with LI-cadherin expression in biliary intraepithelial lesions of ICC without hepatolithiasis, whereas the mucin phenotype or CDX2 expression does not.

Fatty Acid Synthase Expression in Barrett's Esophagus

To investigate the relationship between fatty acid synthase (FASN) expression and the clinicopathological characteristics of Barrett's esophagus and its carcinogenesis. FASN, a key enzyme of the fatty acid biosynthetic pathway, is overexpressed not only in various types of cancer, but also in premalignant conditions. Therefore, FASN overexpression is considered to be indicative of a possible premalignant stage. Patients (N=354) with endoscopically and histologically proven Barrett's esophagus were enrolled. Mucin phenotyping of Barrett's esophagus, expression of FASN and COX-2, cellular proliferation, and apoptosis were evaluated immunohistochemically in biopsy samples, and factors influencing FASN expression were determined by multivariate logistic regression analysis. To evaluate if gastric reflux induces FASN expression, esophageal adenocarcinoma cells were treated with bile acid and low pH, and the effect of a FASN inhibitor on cell proliferation was assessed. Expression of FASN protein was observed in 52.2% of patients with Barrett's esophagus by immunohistochemistry; this expression pattern was retained in esophageal adenocarcinoma. Intestinal mucin phenotype, COX-2, increased stromal angiogenesis, and elevated proliferating cell nuclear antigen index were confirmed to be positive independent factors for FASN expression. In the esophageal adenocarcinoma cell line SEG-1, FASN mRNA was induced by bile acid with low pH. Cell proliferation was strongly suppressed by the FASN inhibitor C75. FASN is strongly expressed in the intestinal mucin phenotype of Barrett's esophagus, in which Barrett's glandular cells display elevated cellular proliferation, angiogenesis, and COX-2 expression. Exposure of the lower esophagus to bile acid with low pH may induce FASN in Barrett's esophagus.

Gastric mucin and beta-catenin are useful markers to predict submucosal invasion and lymph node metastasis in intestinal type early gastric cancer

Background and aim: With the increasing therapeutic use of endoscopic resection for intestinal early gastric cancer (EGC), it is very important to predict biological behaviors of intestinal type EGC prior to endoscopic resection. On this background, we tried to elucidate the presumptive clinicopathologic factors and biologic markers to predict submucosal invasion and lymph node metastasis based on mucin expression in EGCs. Methods: One hundred and thirty cases of intestinal EGCs were divided as EGCs with intestinal mucin phenotypes (EGC-IPs) and EGCs with gastric mucin phenotypes (EGC-GPs) based on mucin expression. The expressions of mucins (Muc2, Muc5Ac, Muc6, CD10), other protein markers (p53, CDX2, beta-catenin, E-cadherin, Smad4) by immunohistochemistry were studied. Results: EGC-IPs showed significantly increased p53 expression, CDX2 expression and beta-catenin delocalization than EGC-GPs. Using binary logistic regression analysis, expression of both gastric mucin and nuclear beta-catenin expression could be independent predictive factors of lymph node metastasis and submucosal invasion in intestinal EGCs. Lymphovascular emboli, and size of lesion could be clinicopathological independent predictive factors of lymph node metastasis and submucosal invasion in intestinal EGCs, respectively. Conclusions: Taken together, we suggest that beta-catenin expression based on mucin phenotype might be used to predict biologic behavior prior to endoscopic mucosal resection in intestinal EGC.

Gastric cancer following total proctocolectomy for colon cancer associated with ulcerative colitis.

Here we report a case of advanced gastric cancer seen after total proctocolectomy for an early colon cancer associated with ulcerative colitis (UC). A 42-year-old man, diagnosed with UC at the age of 21, had undergone total proctocolectomy at the age of 38 for an early ascending colon cancer. Three years later the patient developed tarry stools and epigastric discomfort. Laboratory data showed anemia together with elevated serum p53 antibody. Gastric endoscopy showed thickening folds around a lesion in the stomach body. The pathological diagnosis was poorly differentiated adenocarcinoma with signet-ring cell carcinoma. Total gastrectomy was performed and the resected specimens showed a diffuse infiltrating tumor (scirrhous gastric carcinoma), 11×15cm in size, with multiple lymph node metastases. Histopathological examination revealed diffuse infiltration of cancer cells throughout the gastric wall and invasion of the serosa. Results of cytology on abdominal lavage were positive for cancer cells. Likewise, immunohistochemical staining showed gastric mucin phenotype cancer cells positive for p53. In conclusion, it is important to bear in mind that patients with UC, especially chronically active pancolitis, potentially bear the risk of upper gastrointestinal complications.

MicroRNA signature analysis in colorectal cancer: identification of expression profiles in stage II tumors associated with aggressive disease

Colorectal cancer (CRC) is a clinically diverse disease whose molecular etiology remains poorly understood. The purpose of this study was to identify miRNA expression patterns predictive of CRC tumor status and to investigate associations between microRNA (miRNA) expression and clinicopathological parameters. Expression profiling of 380 miRNAs was performed on 20 paired stage II tumor and normal tissues. Artificial neural network (ANN) analysis was applied to identify miRNAs predictive of tumor status. The validation of specific miRNAs was performed on 102 tissue specimens of varying stages. Thirty-three miRNAs were identified as differentially expressed in tumor versus normal tissues. ANN analysis identified three miRNAs (miR-139-5p, miR-31, and miR-17-92 cluster) predictive of tumor status in stage II disease. Elevated expression of miR-31 (p = 0.004) and miR-139-5p (p < 0.001) and reduced expression of miR-143 (p = 0.016) were associated with aggressive mucinous phenotype. Increased expression of miR-10b was also associated with mucinous tumors (p = 0.004). Furthermore, progressively increasing levels of miR-10b expression were observed from T1 to T4 lesions and from stage I to IV disease. Association of specific miRNAs with clinicopathological features indicates their biological relevance and highlights the power of ANN to reliably predict clinically relevant miRNA biomarkers, which it is hoped will better stratify patients to guide adjuvant therapy.

Overexpression of carbonic anhydrase IX (CAIX) is an independent unfavorable prognostic marker in endometrioid ovarian cancer

Carbonic anhydrase IX (CAIX) is a strictly membranous expressed metalloenzyme involved in cell adhesion, pH homeostasis, and cancer progression. This study was designed to assess the role of CAIX in primary ovarian cancer. Two hundred five well-characterized primary ovarian carcinomas were analyzed on a tissue microarray. CAIX expression was determined by immunohistochemistry using a four-step scoring system. Moderate and strong membranous CAIX expression was found in 37 out of 205 (18%) of all assessable ovarian cancer specimens. High levels of CAIX expression were related to mucinous and endometrioid phenotype of ovarian carcinomas (p < 0.05). There was no association between CAIX overexpression and tumor stage, grading, and mitotic count of ovarian carcinomas (p > 0.05). In univariate Cox regression analysis, advanced tumor stage (p < 0.01), high tumor grade (p = 0.017), high mitotic count (p = 0.025), and high CAIX expression levels (p = 0.031) were correlated to shorter overall patient survival. High pT stage (p = 0.036) and CAIX overexpression were connected to poor clinical outcome in endometrioid ovarian carcinomas. Multivariate Cox regression hazard analysis comprising tumor stage, tumor grade, mitotic count, and CAIX expression revealed pT2/3 stage and CAIX overexpression (scores 2 and 3) as independent prognostic markers in ovarian cancer (p < 0.01, each) as well as in the subgroup of endometrioid carcinomas (p < 0.05, each). In conclusion, CAIX is overexpressed in a substantial proportion of mucinous and endometrioid ovarian carcinomas and connected to poor patient outcome. Our data support the potential therapeutic benefit of newly developed targeting antibodies in advanced ovarian cancer.

Mucin phenotype and narrow-band imaging with magnifying endoscopy for differentiated-type mucosal gastric cancer

Several studies have described the surface glandular structure in differentiated early gastric cancer observed by narrow-band imaging with magnifying endoscopy (NBI-ME) in two main patterns, i.e., a papillary or granular structure in an intralobular loop pattern (ILL) and a pit structure in a fine network pattern (FNP). However, it is uncertain why the NBI-ME findings of differentiated-type carcinomas are divided into two main patterns. We investigated the significance of the mucin phenotype in the morphogenetic difference between ILL and FNP. We evaluated 120 intramucosal, well- or predominantly well-differentiated tubular adenocarcinomas. In each lesion, one area that showed the predominant pattern of microsurface structures and microvessels was selected and marked by electrocoagulation for a strict comparative study by NBI-ME and pathological investigation. NBI-ME findings were classified into three patterns: ILL, FNP, and intermediate. Mucin phenotypes were judged as gastric, intestinal, or gastrointestinal type by immunohistochemistry. The mucin phenotype was gastric or gastrointestinal type in 24 (92.3%) of 26 ILL lesions. Intestinal phenotype was observed in 22 (84.6%) of 26 FNP lesions. The gastrointestinal phenotype was observed in 50 (73.5%) of 68 intermediate pattern lesions. The mucin phenotype and NBI-ME results were significantly correlated (P<0.001). The mucin phenotype of differentiated early gastric cancer might be involved in morphogenetic differences between the papillary and pit structures visualized by NBI-ME.

Clinicopathological Analysis of Early-Stage Gastric Cancers Detected After Successful Eradication of Helicobacter pylori

The results of a randomized controlled study and meta-analysis study have recently proved that Helicobacter pylori eradication has a preventive effect against the development of metachronous and primary gastric cancer. However, gastric cancer is sometimes detected after successful eradication. There is a lack of study about gastric cancers in eradicated patients. To clarify the characteristics of gastric cancers detected after H. pylori eradication, we analyzed the clinicopathological features of these cancers. The subjects were 18 early-stage gastric cancer specimens resected from 17 patients who had received successful eradication of H. pylori from February 1995 to March 2009. The control group consisted of 36 specimens from noneradicated patients with persistent H. pylori infection who were matched with the subjects in age, sex, and depth of invasion. Clinicopathological features and mucin phenotypes of gastric cancer were clinically and immunohistologically evaluated. The average diameter of gastric cancer was smaller and Ki-67 index was lower in the eradication group. The morphological distribution of depression types was significantly lower in the control group. Immunohistochemical phenotyping revealed that 72.2% of the lesions in the eradicated group were complete gastric type or gastric predominant mixed type, whereas the percentages of gastric type and intestinal type in the control group were similar. Our findings indicate that the clinicopathological characteristics of gastric cancers detected after H. pylori eradication are different from those of gastric cancers in patients with persistent H. pylori infection. H. pylori eradication may suppress intestinalization during the development of gastric cancer.

Aberrant activation-induced cytidine deaminase expression is associated with mucosal intestinalization in the early stage of gastric cancer

Although Helicobacter pylori is a risk factor for gastric cancer (GC), its detailed carcinogenesis remains unclear. Recently, aberrant expression of activation-induced cytidine deaminase (AID) was demonstrated in gastric epithelium with H. pylori infection and seems to cause the accumulation of mutation. This investigation aims to elucidate whether or not AID expression plays an important role in the carcinogenesis of early GC. We examined the correlation between immunohistochemical AID expression and histological characteristics, including pre-existing chronic gastritis and cellular mucin phenotype in 138 cases of intramucosal GC. Furthermore, we investigated the relationship between AID, p53 protein, and β-catenin. The low degree of polymorphonuclear neutrophil activity, and the high degree of glandular atrophy and intestinal metaplasia were significantly correlated with the high levels of AID expression in non-neoplastic mucosa (P = 0.007, P ≤ 0.001, and P = 0.003). With regard to mucin phenotype of carcinoma, the intestinal phenotype tended to have the higher AID expression levels (P = 0.052). AID showed close correlations with Cdx2 and nuclear staining of β-catenin (P = 0.003, P = 0.034). As for p53 protein, no correlation was found with AID expression. Our findings suggest that aberrant AID expression is correlated with persistent inflammatory condition induced by H. pylori infection and may contribute to the development of GC through an inflammatory condition and intestinalization.